Interestingly, in a retrospective study of 170 pregnancies in 96 women with persistent positivity for aPL antibodies, Sciascia et al.89found that HCQ (200400 mg/day) reduced adverse pregnancy outcomes (OR = 2.2; 95% CI = 1.2136), especially fetal losses at > 10 WG (2%vs.11%;P= 0.05) and placentamediated complications, such as PE, placental abruption and IUGR (2%vs11%;P= 0.05). of HCQ are reviewed in anticipation of the results of current and future trials. Two related trials addressing RM in the absence of maternal autoimmune disease are Rabbit Polyclonal to SH3GLB2 ongoing. Other trials addressing pregnancy outcomes in the presence of maternal autoimmune disease are forthcoming. In this review, we hypothesise that this immunological and endothelial effects of HCQ may be beneficial in the context of PE and RM, regardless of the maternal autoimmune status. Keywords:hydroxychloroquine, pregnancy, preeclampsia, recurrent miscarriage == 1. INTRODUCTION == Recurrent miscarriage (RM), defined as 3 consecutive miscarriages, is usually a frequent condition in reproductive medicine, and it affects 1 to 2% of fertile couples. To date, there is no effective treatment for preventing the recurrence of pregnancy loss. Similarly, preeclampsia (PE), defined as PF 477736 concomitant arterial hypertension and significant proteinuria after 20 weeks of gestation (WG), affects approximately 5% of pregnant women worldwide. The only treatment for PE is usually delivery, which needs to be induced early. PE causes maternal and fetal complications, such as premature birth. PE has a high recurrence rate (approximately 20%)1,2and can be only partially prevented by aspirin use. == 2. PATHOPHYSIOLOGY OF PREECLAMPSIA == PE is usually a complex disease with a multifaceted presentation. Some authors have hypothesised the presence of two types of PE: early onset and lateonset PE.3These types share the same pathogenesis but have different inherent maternal characteristics.4,5The precise pathogenesis of PE is unclear. However, the placenta is the organ that triggers PE, and an imbalance in early angiogenesis seems to be a key risk factor for PE. Early onset PE can be explained by impaired early placentation due to an imbalance between growing fetal trophoblasts and maternal endothelial vascular remodelling. Early onset PE is usually mediated by innate immune mechanisms. This was suggested by a study reporting that deficient stimulation of uterine natural killer (NK) cells is usually correlated with the inadequate expression of paternalfetal HLA surfacecell markers.6Under physiological conditions, the invading cytotrophoblasts adopt a vascular PF 477736 adhesion phenotype. The defect in vascular remodelling is the consequence of the deficient transformation of cytotrophoblast surface integrins and adhesion molecules. 7 Lateonset PE may be linked to a preexisting maternal endothelial dysfunction that is associated with obesity, diabetes, chronic hypertension or age >35 years.8,9Longterm cardiovascular complications are associated with lateonset PE. High placental growth factor (PlGF) levels at PE diagnosis have been reported in lateonset PE compared to nonhypertensive pregnancies.10These high PlGF levels have been associated with an increased risk of coronary disease more than 10 years after the PE diagnosis.10Lateonset PE is the most predictable type of PE; thus, its prevention should be a PF 477736 standard therapeutic strategy in the care of nulliparous women. In late pregnancy, placentainduced hypoxemia and its related complications become apparent in both types of PE. This placentainduced hypoxemia leads to the release of numerous placental factors, such as antiangiogenic factors and trophoblastic debris (e.g., syncytiotrophoblast membrane microparticles, fetal soluble DNA and RNA, cytotrophoblast cells), into the maternal circulation.11,12Upregulated antiangiogenic factors (soluble fmslike tyrosine kinase 1 [sFlt1] and soluble endoglin [sEng]) bind to angiogenic factors (VEGF and PlGF) and reduce their bioavailability.13The severity and timing of this angiogenic imbalance, combined with inherent maternal factors, may be the determinants of the clinical presentation of PE.4Moreover, placentainduced hypoxaemia leads to placental oxidative stress,14resulting in mitochondrial PF 477736 dysfunction, NADPH1 upregulation,15and elevated levels of free radicals and oxidised lipids. Lastly, placentainduced hypoxaemia induces apoptosis and adiponecrosis in the placenta. The above effects of placentainduced hypoxia trigger the following maternal responses: (i) a systemic inflammatory response with proinflammatory cytokine production,13,14,15,16lysosomal (tolllike receptor [TLR]2, 4) and extralysosomal (TLR3, 7, 9) TLR activation,17,18,19alterations in the Th1/Th2 balance, the production of agonistic angiotensin II type 1 receptor antibodies20(and hence vasoconstriction via endothelin 1,21the stimulation of NADPH oxidase22and sFlt1 production23) and the activation of the complement system; (ii) the activation of maternal oxidative stress, resulting in endothelial NADPH2 upregulation in women with PE24; and (iii) maternal endothelial dysfunction with increased production of vasoconstrictor molecules25(endothelin 1, thromboxane A2), increased activation of the reninangiotensin system, a decrease in NO, and the overexpression of adhesion molecules (ICAM, VCAM) (leading to the adhesion of monocytes to the endothelium). The clinical presentation of maternal endothelial dysfunction is usually vasoconstriction in the mother manifesting as hypertension and glomerular dysfunction. In addition, severe symptoms can occur either in the mother (HELLP syndrome, disseminated intravascular coagulation,.